Methods and Compositions for Treating Cancer

ABSTRACT

Methods and compositions for treating cancer are described herein. More particularly, the methods for treating cancer comprise administering a 17α-hydroxylase/C 17,20 -lyase inhibitor, such as abiraterone acetate (i.e., 3β-acetoxy-17-(3-pyridyl) androsta-5,16-diene), in combination with at least one additional therapeutic agent such as an anti-cancer agent or a steroid. Furthermore, disclosed are compositions comprising a 17α-hydroxylase/C 17,20 -lyase inhibitor, and at least one additional therapeutic agent, such as an anti-cancer agent or a steroid.

FIELD OF THE INVENTION

Methods and compositions for treating cancer are described herein. Moreparticularly, the methods for treating cancer comprise administering a17α-hydroxylase/C_(17,20)-lyase inhibitor, such as abiraterone acetate(i.e., 3β-acetoxy-17-(3-pyridyl) androsta-5,16-diene), in combinationwith at least one additional therapeutic agent, such as an anti-canceragent or a steroid. Furthermore, disclosed are compositions comprising a17α-hydroxylase/C_(17,20)-lyase inhibitor, and at least one additionaltherapeutic agent such as an anti-cancer agent or a steroid, e.g., acorticosteroid or, more specifically, a glucocorticoid.

BACKGROUND

The number of people diagnosed with cancer has significantly increased.Of special interest are individuals diagnosed with androgen-dependentdisorders, such as prostate cancer, and estrogen-dependent disorders,such as breast cancer since such diagnoses are increasing in number atan alarming rate.

Prostate cancer is currently the most common non-skin cancer and thesecond leading cause of cancer-related death in men after lung cancer.The primary course of treatment for patients diagnosed withorgan-confined prostate cancer is usually prostatectomy or radiotherapy.Not only are these treatments highly invasive and have undesirable sideeffects, such localized treatments are not effective on prostate cancerafter it has metastasized. Moreover, a large percent of individuals whoreceive localized treatments will suffer from recurring cancer.

Additionally, breast cancer incidence in women has increased from oneout of every 20 women in 1960 to one out of every eight women in 2005.Moreover, it is the most common cancer among white and African-Americanwomen. Similar to treating prostate cancer, most options for womendiagnosed with breast cancer are highly invasive and have significantside-effects. Such treatments include surgery, radiation andchemotherapy.

Hormone therapy is another treatment option for individuals diagnosedwith prostate or breast cancer. Hormone therapy is a form of systemictreatment for prostate or breast cancer wherein hormone ablation agentsare used to suppress the production or block the effects of hormones,such as estrogen and progesterone in the body, which are believed topromote the growth of breast cancer, as well as testosterone anddihydrotestosterone, which are believed to promote the growth ofprostate cancer. Moreover, hormone therapy is less invasive than surgeryand does not have many of the side effects associated with chemotherapyor radiation. Hormone therapy can also be used by itself or in additionto localized therapy and has shown to be effective in individuals whosecancer has metastasized.

Even though hormone therapy is less invasive and can be used on moreadvanced stages of cancer, some individuals administered current hormonetherapy treatments may not show a significant response or may not showany response at all to such treatments. Additionally, some patientstreated with current hormone therapy treatments may also suffer fromrelapsing or recurring cancer. Currently, such refractory cancerpatients are left with very few treatment options.

Despite the progress made in the treatment of cancer, there remains aneed for more effective ways to treat cancer such as, but not limitedto, prostate cancer and breast cancer. Additionally, there is a need foreffective anti-cancer treatment options for patients who are notresponding to current anti-cancer treatments. Also, there is a need foreffective anti-cancer treatment options fir patients whose cancer hasrecurred.

SUMMARY OF THE INVENTION

Described herein are methods for treating a cancer in which atherapeutically effective amount of a 17α-hydroxylase/C_(17,20)-lyaseinhibitor, such as abiraterone acetate (i.e.3β-acetoxy-17-(3-pyridyl)androsta-5,16-diene), is administered to apatient, e.g., a patient in need thereof, in combination with atherapeutically effective amount of at least one additional therapeuticagent including, but not limited to, an anti-cancer agent or steroid.Such methods can also provide an effective treatment for individualswith a refractory cancer, including individuals who are currentlyundergoing a cancer treatment. Therefore, in certain embodiments, themethod is directed to treating a refractory cancer in a patient, inwhich a therapeutically effective amount of17α-hydroxylase/C_(17,20)-lyase inhibitor is administered to a patientcurrently receiving an anti-cancer agent.

For example, in certain embodiments, the method for the treatment of acancer in a mammal comprises administering an amount of about 0.01mg/kg/day to about 100 mg/kg/day of abiraterone acetate and an amount ofabout 0.1 mg/m² to about 20 mg/m² of mitoxantrone.

In another embodiment, the method for the treatment of a cancer in amammal comprises administering an amount of about 0.01 mg/kg/day toabout 100 mg/kg/day of abiraterone acetate and an amount of about 1mg/m² to about 175 mg/m² of paclitaxel.

In still other embodiments, the method for the treatment of a cancer ina mammal comprises administering an amount of about 0.01 mg/kg/day toabout 10 mg/kg/day of abiraterone acetate and an amount of about 1 mg/m²to about 100 mg/m² of docetaxel.

Furthermore, described herein is a method for the treatment of a cancerin a mammal comprising administering an amount of about 0.01 mg/kg/dayto about 100 mg/kg/day of abiraterone acetate; and an amount of about0.01 mg to about 200 mg of leuprolide, wherein the leuprolide isadministered over a period of about 3 days to about 12 months.

In other embodiments, the method for the treatment of a cancer in amammal comprises administering an amount of about 0.01 mg/kg/day toabout 100 mg/kg/day of abiraterone acetate and an amount of about 0.01mg to about 20 mg of goserelin, wherein the goserelin is administeredover a period of about 28 days to about 3 months.

Additionally, in another embodiment, the method for the treatment of acancer in a mammal comprises administering an amount of about 0.01mg/kg/day to about 100 mg/kg/day of abiraterone acetate and an amount ofabout 0.01 mg to about 20 mg of triptorelin, wherein the triptorelin isadministered over a period of about 1 month.

The method for the treatment of a cancer in a mammal can also compriseadministering an amount of about 0.01 mg/kg/day to about 100 mg/kg/dayof abiraterone acetate and an amount of about 0.1 μg/day to about 500μg/day of seocalcitol, such as about 100 μg/day of seocalcitol.

Also, the method for the treatment of a cancer in a mammal can compriseadministering an amount of about 0.01 mg/kg/day to about 100 mg/kg/dayof abiraterone acetate and an amount of about 1 mg/day to about 300mg/day of bicalutamide.

In yet another embodiment, the method for the treatment of a cancer in amammal can comprise administering an amount of about 0.01 mg/kg/day toabout 100 mg/kg/day of abiraterone acetate and an amount of about 1mg/day to about 2000 mg/day of flutamide.

Moreover, the method for the treatment of a cancer in a mammal cancomprise administering an amount of about 50 mg/day to about 2000 mg/dayof abiraterone acetate and an amount of about 0.01 mg/day to about 500mg/day of a glucocorticoid including, but not limited to,hydrocortisone, prednisone or dexamethasone.

Also described herein are compositions for the treatment of cancer thatcomprise a combination of a therapeutically effective amount of at leastone 17α-hydroxylase/C_(17,20)-lyase inhibitor and a therapeuticallyeffective amount of at least one additional anti-cancer agent, such as,but not limited to, mitoxantrone, paclitaxel, docetaxel, leuprolide,goserelin, triptoelin, seocalcitol, bicalutamide, flutamide, or asteroid including, but not limited to, hydrocortisone, prednison, ordexamethasone.

Finally, single unit dosage forms comprising abiraterone acetate and aglucocorticoid, optionally with carriers, diluents or excipients, arecontemplated. Also, kits comprising at least one17α-hydroxylase/C_(17,20)-lyase inhibitor and an additional anti canceragent or steroid are contemplated. For example, the kit may include avial containing abiraterone acetate and another vial containing aglucocorticoid.

DEFINITIONS

As used herein and unless otherwise defined the word “cancer,” refers tothe growth, division or proliferation of abnormal cells in the body.Cancers that can be treated with the methods and the compositionsdescribed herein include, but are not limited to, prostate cancer,breast cancer, adrenal cancer, leukemia, lymphoma, myeloma,Waldenström's macroglobulinemia, monoclonal gammopathy, benignmonoclonal gammopathy, heavy chain disease, bone and connective tissuesarcoma, brain tumors, thyroid cancer, pancreatic cancer, pituitarycancer, eye cancer, vaginal cancer, vulvar cancer, cervical cancer,uterine cancer, ovarian cancer, esophageal cancer, stomach cancer, coloncancer, rectal cancer, liver cancer, gallbladder cancer,cholangiocarcinoma, lung cancer, testicular cancer, penal cancer, oralcancer, skin cancer, kidney cancers, Wilms' tumor and bladder cancer.

As used herein, and unless otherwise defined, the terms “treat.”“treating” and “treatment” include the eradication, removal,modification, management or control of a tumor or primary, regional, ormetastatic cancer cells or tissue and the minimization or delay of thespread of cancer.

As used herein, and unless otherwise defined, the term “patient” meansan animal, including but not limited to an animal such as a human,monkey, cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse,rat, rabbit, or guinea pig. In one embodiment, the patient is a mammaland in another embodiment the patient is a human. In certainembodiments, the patient can be an adult male or female. In someembodiments, the patient is a male of age about 30 years to about 85years. In other embodiments, the patient is a female of age about 30years to about 85 years. In a particular embodiment, the patient has oris susceptible to having (e.g., through genetic or environmentalfactors) cancer. In a further embodiment, the patient has or issusceptible to having (e.g., through genetic or environmental factors) atumor. In other embodiments, the patient can be castrated ornon-castrated.

The term “17α-hydroxylase/C_(17,20)-lyase inhibitor” as used hereinrefers to an inhibitor of 17α-hydroxylase/C_(17,20)-lyase, (which is anenzyme in testosterone synthesis), an analog thereof, derivativethereof, metabolite thereof or pharmaceutically acceptable salt thereof.Also, unless otherwise noted, reference to a particular17α-hydroxylase/C_(17,20)-lyase inhibitor can include analogs,derivatives, metabolites or pharmaceutically acceptable salts of suchparticular 17α-hydroxylase/C_(17,20)-lyase inhibitor.

The term “anti-cancer agent” as used herein refers to any therapeuticagent that directly or indirectly kills cancer cells or directly orindirectly prohibits stops or reduces the proliferation of cancer cells.It should be noted that even though throughout this specification and inthe claims the phrase “anti-cancer agent” is written as a singular noun,for example; “an anti-cancer agent” or “the anti-cancer agent,” thephrase “anti-cancer agent” should not be interpreted as being limited tothe inclusion of a single anti-cancer agent.

As used herein, and unless otherwise defined, the phrase“therapeutically effective amount” when used in connection with a17α-hydroxylase/C_(17,20)-lyase inhibitor or therapeutic agent means anamount of the 17α-hydroxylase/C_(17,20)-lyase inhibitor or therapeuticagent effective for treating a disease or disorder disclosed herein,such as cancer.

As used herein and unless otherwise defined the phrase “refractorycancer.” means cancer that is not responding to an anti-cancer treatmentor cancer that is not responding sufficiently to an anti-cancertreatment. Refractory cancer can also include recurring or relapsingcancer.

As used herein and unless otherwise defined the phrase “refractorypatient,” means a patient who has refractory cancer.

As used herein and unless otherwise defined the phrase “relapse cancer.”means cancer that was at one time responsive to an anti-cancer treatmentbut has become no longer responsive to such treatment or is no longerresponding sufficiently to such treatment.

As used herein and unless otherwise defined the phrase “recurringcancer,” means cancer that has returned after a patient has been earlierdiagnosed with cancer, under gone treatment or had been previouslydiagnosed as cancer-free.

As used herein and unless otherwise defined the term “derivative” refersto a chemically modified compound wherein the chemical modificationtakes place at one or more functional groups of the compound. Thederivative may retain or improve the pharmacological activity of thecompound from which it is derived.

As used herein and unless otherwise defined the term “analog” refers toa chemical compound that is structurally similar to another but differsslightly in composition (as in the replacement of one atom by an atom ofa different element or in the presence of a particular functionalgroup).

As used herein and unless otherwise defined the phrase “pharmaceuticallyacceptable salt” refers to any salt of a 17α-hydroxylase/C_(17,20)-lyaseinhibitor which retains the biological effectiveness of the17α-hydroxylase/C_(17,20)-lyase inhibitor. Examples of pharmaceuticallyacceptable salts include, but are not limited to, acetates, sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, gamma-hydroxybutyrates, glycollates, tartarates,alkanesulfonates (e.g. methane-sulfonate or mesylate),propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates,and mandelates. Several of the officially approved salts are listed inRemington: The Science and Practice of Pharmacy, Mack Publ. Co., Easton.

DETAILED DESCRIPTION OF THE INVENTION

The methods described herein for treating cancer comprise administeringto a mammal, preferably a human, a 17α-hydroxylase/C_(17,20)-lyaseinhibitor in addition to at least one therapeutic agent, such as ananti-cancer agent or steroid, particularly a glucocorticoid. Thecompositions described herein comprise a 17α-hydroxylase/C_(17,20)-lyaseinhibitor and at least one additional therapeutic agent, such as ananti-cancer agent or steroid, particularly a corticosteroid orglucocorticoid. Other anti-cancer treatments such as, administration ofyet another anti-cancer agent, radiotherapy, chemotherapy, photodynamictherapy, surgery or other immunotherapy, can be used with the methodsand compositions.

17α-hydroxylase/C_(17,20)-lyase Inhibitors

17α-hydroxylase/C_(17,20)-lyase inhibitors have been shown to be usefulin the treatment of cancer, specifically hormone-dependent disorderssuch as, androgen-dependent and estrogen-dependent disorders likeprostate cancer and breast cancer respectively, as described in U.S.Pat. No. 5,604,213 to Barrie et al., which is herein incorporated byreference in its entirety.

In certain embodiments, the 17α-hydroxylase/C_(17,20)-lyase inhibitorcan be 17-(3-pyridyl)androsta-5,16-dien-3β-ol;17-(3-pyridyl)androsta-3,5,16-triene;17-(3-pyridyl)androsta-4,16-dien-3-one;17-(3-pyridyl)estra-1,3,5[10],16-tetraen-3-ol;17-(3-pyridyl)-5α-androst-16-en-3α-ol;17-(3-pyridyl)-5α-androst-16-en-3-one;17-(3-pyridyl)-androsta-4,16-diene-3,11-dione;17-(3-pyridyl)-androsta-3,5,16-trien-3-ol; 6α- and6β-fluoro-7-(3-pyridyl)androsta-4,16-dien-3-one;17-(3-pyridyl)androsta-4,16-dien-3,6-dione;3α-trifluoromethyl-17-(3-pyridyl)androst-16-en-3β-ol or their acidaddition salts and 3-esters as well as metabolites, analogs, derivativesor a pharmaceutically acceptable salt thereof.

In certain embodiments, the 17α-hydroxylase/C_(17,20)-lyase inhibitorcan have the structure of formula (I):

wherein X represents the residue of the A, B and C rings of a steroidwhich can be, without limitation, androstan-3α- or 3β-ol;androst-5-en-3α- or 3β-ol; androst-4-en-3-one; androst-2-ene;androst-4-ene; androst-5-ene; androsta-5,7-dien-3α or 3β-ol;androsta-1,4-dien-3-one; androsta-3,5-diene; androsta-3,5-diene-3-ol;estra-1,3,5[10]-triene; estra-1,3,5[10]-trien-3-ol; 5α-androstan-3-one;androst-4-ene-3,11-dione; 6-fluoroandrost-4-ene-3-one; orandrostan-4-ene-3,6-dione; each of which, where structurallypermissible, can be further derivatized in one or more of the followingways, including, but not limited to, to form 3-esters; to have one ormore carbon or carbon ring double bonds in any of the 5,6-, 6,7-, 7,8-,9,11- and 11,12-positions; as 3-oximes; as 3-methylenes; as3-carboxylates; as 3-nitriles; as 3-nitros; as 3-desoxy derivatives; tohave one or more hydroxy, halo, C₁₋₄-alkyl, trifluoromethyl,C₁₋₄-alkoxy, C₁₋₄-alkanoyloxy, benzoyloxy, oxo, methylene or alkenylsubstituents in the A, B, or C-ring; or to be 19-nor;

R represents a hydrogen atom or an alkyl group of 1-4 carbon atoms;

R¹⁴ represents a hydrogen atom, a halogen atom or an alkyl group of 1 to4 carbon atoms;

-   -   each of the R¹⁵ substituents independently represents a hydrogen        atom or an alkyl or alkoxy group of 1-4 carbon atoms, a hydroxy        group or an alkylcarbonyloxy group of 2 to 5 carbon atoms or        together represent an oxo or methylene group or R¹⁴ and one of        the R¹⁵ groups together represent a double bond and the other        R¹⁵ group represents a hydrogen atom or an alkyl group of 1 to 4        carbon atoms; and    -   R¹⁶ represents a hydrogen atom, halogen atom, or an alkyl group        of 1 to 4 carbon atoms, in the form of the free bases or        pharmaceutically acceptable acid addition salts, but excluding        3β-acetoxy-17-(3-pyridyl)androsta-5,14,16-triene, 3β,15α- and        3β,15β-diacetoxy-17-(3-pyridyl)androsta-5,16-diene and        3β-methoxy-17-(3-pyridyl-5α-andros-16-ene. Suitable inhibitors        also include metabolites, derivatives, analogs, or        pharmaceutically acceptable salts of formula (I).

In another embodiment, the 17α-hydroxylase/C_(17,20)-lyase inhibitor canhave the structure of formula (I):

wherein R represents hydrogen or a lower acyl group having 1 to 4carbons. Suitable inhibitors also include derivatives, analogs, orpharmaceutically acceptable salts of formula (I).

In still another embodiment, the 17α-hydroxylase/C_(17,20)-lyaseinhibitor can be a 3α-alkanoyloxy-17-(3-pyridyl) androsta-5, 16-diene inwhich the alkanoyloxy group has from 2 to 4 carbon atoms.

In a preferred embodiment, the 17α-hydroxylase/C_(17,20)-lyase inhibitorcomprises abiraterone acetate or3β-acetoxy-17-(3-pyridyl)androsta-5,16-diene which has the followingstructural formula:

and pharmaceutically acceptable salts thereof.

Preferred salts of abiraterone acetate and methods of making such saltsare also disclosed in U.S. Provisional Application No. 60/603,559 toHunt, which is incorporated by reference in its entirety. Preferredsalts include, but are not limited to, acetates, citrates, lactates,alkanesulfonates (e.g. methane-sulfonate or mesylate) and tartarates. Ofspecial interest is the abiraterone acetate mesylate salt (i.e.3β-acetoxy-17-(3-pyridyl)androsta-5,16-diene mesylate salt) which hasthe following structural formula:

The 17α-hydroxylase/C_(17,20)-lyase inhibitors can be made according toany method known to one skilled in the art. For example, such inhibitorscan be synthesized according to the method disclosed in U.S. Pat. Nos.5,604,213 and 5,618,807 to Barrie et al., herein incorporated byreference. Another method of making 17α-hydroxylase/C_(17,20)-lyaseinhibitors is disclosed in U.S. provisional application 60/603,558 toBury, herein incorporated by reference.

The amount of 17α-hydroxylase/C_(17,20)-lyase inhibitor administered toa mammal having cancer is an amount that is sufficient to treat thecancer, whether the 17α-hydroxylase/C_(17,20)-lyase inhibitor isadministered alone or in combination with an additional anti-cancertreatment, such as an additional anti-cancer agent.

Additional Therapeutic Agents

Suitable compounds that can be used in addition to17α-hydroxylase/C_(17,20)-lyase inhibitors as an anti-cancer agentinclude, but are not limited to, hormone ablation agents, anti-androgenagents, differentiating agents, anti-neoplastic agents, kinaseinhibitors, anti-metabolite agents, alkylating agents, antibioticagents, immunological agents, interferon-type agents, intercalatingagents, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, mitoticinhibitors, matrix metalloprotease inhibitors, genetic therapeutics, andanti-androgens. The amount of the additional anti-cancer agentadministered to a mammal having cancer is an amount that is sufficientto treat the cancer whether administered alone or in combination with a17α-hydroxylase/C_(17,20)-lyase inhibitor. Below are lists of examplesof some of the above classes of anti-cancer agents. The examples are notall inclusive and are for purposes of illustration and not for purposesof limitation. Many of the examples below could be listed in multipleclasses of anti-cancer agents and are not restricted in any way to theclass in which they are listed in.

Suitable hormonal ablation agents include, but are not limited to,androgen ablation agents and estrogen ablation agents. In preferredembodiments, the 17α-hydroxylase/C_(17,20)-lyase inhibitor isadministered with a hormonal ablation agent, such as deslorelin,leuprolide, goserelin or triptorelin. Even though throughout thisspecification and in the claims the phrase “hormonal ablation agent” iswritten as a singular noun, for example; “a hormonal ablation agent” or“the hormonal ablation agent,” the phrase “hormonal ablation agent”should not be interpreted as being limited to the inclusion of a singlehormonal ablation agent. The amount of the hormonal ablation agentadministered to a mammal having cancer is an amount that is sufficientto treat the cancer whether administered alone or in combination with a17α-hydroxylase/C_(17,20)-lyase inhibitor.

Suitable anti-androgen agents include but are not limited tobicalutamide, flutamide and nilutamide. The amount of the anti-androgenagent administered to a mammal having cancer is an amount that issufficient to treat the cancer whether administered alone or incombination with a 17α-hydroxylase/C_(17,20)-lyase inhibitor.

In another embodiment, the 17α-hydroxylase/C_(17,20)-lyase inhibitor maybe administered with a differentiating agent. Suitable differentiatingagents include, but are not limited to, polyamine inhibitors; vitamin Dand its analogs, such as, calcitriol, doxcrcalciferol and seocalcitol;metabolites of vitamin A, such as, ATRA, retinoic acid, retinoids;short-chain fatty acids; phenylbutyrate; and nonsteroidalanti-inflammatory agents. The amount of the differentiating agentadministered to a mammal having cancer is an amount that is sufficientto treat the cancer whether administered alone or in combination with a17α-hydroxylase/C_(17,20)-lyase inhibitor.

In another preferred embodiment, the 17α-hydroxylase/C_(17,20)-lyaseinhibitor may be administered with an anti-neoplastic agent, including,but not limited to, tubulin interacting agents, topoisomerase inhibitorsand agents, acitretin, alstonine, amonafide, amphethinile, amsacrine,ankinomycin, anti-neoplaston, aphidicolin glycinate, asparaginase,baccharin, batracylin, benfluron, benzotript, bromofosfamide,caracemide, carmethizole hydrochloride, chlorsulfaquinoxalone,clanfenur, claviridenone, crisnatol, curaderm, cytarabine, cytocytin,dacarbazine, datelliptinium, dihaematoporphyrin ether, dihydrolenperone,dinaline, distamycin, docetaxel, elliprabin, elliptinium acetate,epothilunes, ergotamine, etoposide, etretinate, fenretinide, galliumnitrate, genkwadaphnin, hexadecylphosphocholine, homoharringtonine,hydroxyurea, ilmofosine, isoglutamine, isotretinoin, leukoregulin,lonidamine, merbarone, merocyanlne derivatives, methylanilinoacridine,minactivin, mitonafide, mitoquidone, mitoxantrone, mopidamol,motretinide, N-(retinoyl)amino acids, N-acylated-dehydroalanines,nafazatrom, nocodazole derivative, ocreotide, oquizanocine, paclitaxcl,pancratistatin, pazelliptine, piroxantrone, polyhaematoporphyrin,polypreic acid, probimane, procarazine, proglumide, razoxane,retelliptine, spatol, spirocyclopropane derivatives, spirogermanium,strypoldinone, superoxide dismutase, teniposide, thaliblastine,tocotrienol, topotecan, ukrain, vinblastine sulfate, vincristine,vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, andwithanolides. The amount of the anti-neoplastic agent administered to amammal having cancer is an amount that is sufficient to treat the cancerwhether administered alone or in combination with a17α-hydroxylase/C_(17,20)-lyase inhibitor.

The 17α-hydroxylase/C_(17,20)-lyase inhibitors may also be used with akinase inhibitor including p38 inhibitors and CDK inhibitors. TNFinhibitors, metallomatrix proteases inhibitors (MMP), COX-2 inhibitorsincluding celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib,SOD mimics or α_(v)β₃ inhibitors. The amount of the kinase inhibitoradministered to a mammal having cancer is an amount that is sufficientto treat the cancer whether administered alone or in combination with a17α-hydroxylase/C_(17,20)-lyase inhibitor.

In another embodiment, the 17α-hydroxylase/C_(17,20)-lyase inhibitor maybe administered with an anti-metabolite agent. Suitable anti-metaboliteagents may be selected from, but not limited to, 5-FU-fibrinogen,acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur,cyclopentyl cytosine, cytarabine phosphate stearate, cytarabineconjugates, dezaguanine, dideoxycytidine, dideoxyguanosine, didox,doxifluridine, fazarabine, floxuridine, fludarabine phosphate,5-fluorouracil, N-(2′-furanidyl)-5-fluorouracil, isopropyl pyrrolizine,methobenzaprim, methotrexate, norspermidine, pentostatin, piritrexim,plicamycin, thioguanine, tiazofurin, trimetrexate, tyrosine kinaseinhibitors, and uricytin. The amount of the anti-metabolite agentadministered to a mammal having cancer is an amount that is sufficientto treat the cancer whether administered alone or in combination with a17α-hydroxylase/C_(17,20)-lyase inhibitor.

In another embodiment, the 17α-hydroxylase/C_(17,20)-lyase inhibitor maybe administered with an alkylating agent. Suitable alkylating agents maybe selected from, but not limited to, aldo-phosphanide analogues,altretamine, anaxirone, bestrabucil, budotitane, carboplatin,carmustine, chlorambucil, cisplatin, cyclophosphamide, cyplatate,diphenylspiromustine, diplatinum cytostatic, elmustine, estramustinephosphate sodium, fotemustine, hepsul-fam, ifosfamide, iproplatin,lomustine, mafosfamide, mitolactol, oxaliplatin, prednimustine,ranimustine, semustine, spiromustine, tauromustine, temozolomide,teroxirone, tetraplatin and trimelamol. The amount of the alkylatingagent administered to a mammal having cancer is an amount that issufficient to treat the cancer whether administered alone or incombination with a 17α-hydroxylase/C_(17,20)-lyase inhibitor.

In another preferred embodiment, the 17α-hydroxylase/C_(17,20)-lyaseinhibitor may be administered with an antibiotic agent. Suitableantibiotic agents may be selected from, but not limited to, aclarubicin,actinomycin D, actinoplanone, adriamycin, aeroplysinin derivative,amrubicin, anthracycline, azino-mycin-A, bisucaberin, bleomycin sulfate,bryostatin-1, calichemycin, chromoximycin, dactinomycin, daunorubicin,ditrisarubicin B, dexamethasone, doxorubicin, doxorubicin-fibrinogen,elsamicin-A, epirubicin, erbstatin, esorubicin, esperamicin-Al,esperamicin-Alb, fostriecin, glidobactin, gregatin-A, grincamycin,herbimycin, corticosteroids such as hydrocortisone, idarubicin,illudins, kazusamycin, kesarirhodins, menogaril, mitomycin, neoenactin,oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin,prednisone, prednisolone, pyrindanycin A, rapamycin, rhizoxin,rodorubicin, sibanomicin, siwenmycin, sorangicin-A, sparsomycin,talisomycin, tcrpentccin, thrazine, tricrozarin A, and zorubicin. Theamount of the antibiotic agent administered to a mammal having cancer isan amount that is sufficient to treat the cancer whether administeredalone or in combination with a 17α-hydroxylase/C_(17,20)-lyaseinhibitor.

Alternatively, the 17α-hydroxylase/C_(17,20)-lyase inhibitors may alsobe used with other anti-cancer agents, including but not limited to,acemannan, aclarubicin, aldesleukin, alemtuzumab, alitretinoin,altretamine, amifostine, amsacrine, anagrelide, anastrozole, ancestim,bexarotene, broxuridine, capecitabine, celmoleukin, cetrorelix,cladribine, clotrimazole, daclizumab, dexrazoxane, dilazep, docosanol,doxitluridine, bromocriptine, carmustine, cytarabine, diclofenac,edelfosine, edrecolomab, eflornithine, emitefur, exemestanc, exisulind,fadrozole, filgrastim, finasteride, fludarabine phosphate, formestane,fotemustine, gallium nitrate, gemcitabine, glycopine, heptaplatin,ibandronic acid, imiquimod, iobenguane, irinotecan, irsogladine,lanreotide, leflunomide, lenograstim, lentinan sulfate, letrozole,liarozole, lobaplatin, lonidamine, masoprocol, melarsoprol,metoclopramide, mifepristone, miltefosine, mirimostim, mitoguazone,mitolactol, molgramostim, nafarelin, nartograstim, nedaplatin,nilutamide, noscapine, oprelvekin, osaterone, oxaliplatin, pamidronicacid, pegaspargase, pentosan polysulfate sodium, pentostatin, picibanil,pirarubicin, porfimer sodium, raloxifene, raltitrexed, rasburicase,rituximab, romurtide, sargramostim, sizofiran, sobuzoxane, sonermin,suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide,teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropinalfa, topotecan, toremifene, trastuzumab, treosulfim, tretinoin,trilostane, trimetrexate, ubenimex, valrubicin, verteporfin,vinorelbine. The amount of the anti-cancer agent administered to amammal having cancer is an amount that is sufficient to treat the cancerwhether administered alone or in combination with a17α-hydroxylase/C_(17,20)-lyase inhibitor.

The 17α-hydroxylase/C_(17,20)-lyase inhibitors may also be administeredor combined with steroids, such as corticosteroids or glucocorticoids.The 17α-hydroxylase/C_(17,20)-lyase inhibitors and the steroid may beadministered in the same or in different compositions. Non-limitingexamples of suitable steroids include hydrocortisone, prednisone, ordexamethasone. The amount of the steroid administered to a mammal havingcancer is an amount that is sufficient to treat the cancer whetheradministered alone or in combination with a17α-hydroxylase/C_(17,20)-lyase inhibitor.

In one embodiment, provided herein are methods and compositionscomprising both abiraterone acetate and a steroid particularly acorticosteroid, or more particularly a glucocorticoid. Steroids withinthe scope of the disclosure include, but are not limited to, (1)hydrocortisone (cortisol; cyprionate (e.g., CORTEF), oral; sodiumphosphate injection (HYDROCORTONE PHOSPHATE); sodium succinate (e.g.,A-HYDROCORT, Solu-CORTEF), cortisone acetate oral or injection forms,etc.), (2) dexamethasone (e.g., Decadron, oral; Decadron-LA injection,etc.), (3) prednisolone (e.g., Delta-CORTEF, prednisolone acetate(ECONOPRED), prednisolone sodium phosphate (HYDELTRASOL), prednisolonetebutate (HYDELTRA-TBA, etc.)), or (4) prednisone (e.g., DELTASONE,etc.) and combinations thereof. See. e.g., (GOODMAN & GILMAN'S THEPHARMACOLOGICAL BASIS OF THERAPEUTICS, 10^(TH) EDITION 2001.

In a specific embodiment, single unit solid oral dosage forms whichcomprise an amount from about 50 mg to about 300 mg of abirateroneacetate and an amount from about 0.5 mg to about 3.0 mg of a steroid,e.g., glucocorticoid in a single composition, optionally withexcipients, carriers, diluents, etc. is contemplated. For instance, thesingle unit dosage form can comprise about 250 mg of abiraterone acetateand about 1.0 mg, 1.25 mg, 1.5 mg, or 2.0 mg of a steroid, such as butnot limited to corticosteroids or glucocorticoids.

Administration of the 17α-hydroxylase/C_(17,20)-lyase Inhibitor and anAdditional Therapeutic Agent

The 17α-hydroxylase/C_(17,20)-lyase inhibitor and the additionaltherapeutic agent, such as an anti-cancer agent or a steroid can beadministered by any method known to one skilled in the art. In certainembodiments, the 17α-hydroxylase/C_(17,20)-lyase inhibitor and theadditional therapeutic agent can be in separate compositions prior toadministration. In the alternative, the 17α-hydroxylase/C_(17,20)-lyaseinhibitor and the additional therapeutic agent can be combined into asingle composition for administration.

The 17α-hydroxylase/C_(17,20)-lyase inhibitor and the additionaltherapeutic agent can be administered sequentially or simultaneously. Ifadministered sequentially, the order of administration is flexible. Forinstance, 17α-hydroxylase/C_(17,20)-lyase inhibitor acetate can beadministered prior to administration of the additional therapeuticagent. Alternatively, administration of the additional therapeutic agentcan precede administration of 17α-hydroxylase/C_(17,20)-lyase inhibitor.

Whether they are administered as separate compositions or in onecomposition, each composition is preferably pharmaceutically suitablefor administration. Moreover, the 17α-hydroxylase/C_(17,20)-lyaseinhibitor and the therapeutic agent, if administered separately, can beadministered by the same or different modes of administration. Examplesof modes of administration include parenteral (e.g., subcutaneous,intramuscular, intraorbital, intracapsular, intraspinal, intrasternal,intravenous, intradermal, intraperitoneal, intraportal, intra-arterial,intrathecal, transmucosal, intra-articular, and intrapleural,),transdermal (e.g., topical), epidural, and mucosal (e.g., intranasal)injection or infusion, as well as oral, inhalation, pulmonary, andrectal administration. In specific embodiments, both are oral.

For example, the 17α-hydroxylase/C_(17,20)-lyase inhibitor can beadministered transdermally and the additional therapeutic agent can beadministered parenterally. Alternatively, the17α-hydroxylase/C_(17,20)-lyase inhibitor can be administered orally,such as in a tablet, caplet or capsule, while the additional therapeuticagent can be administered intravenously. Such intravenous administeredtherapeutic agents include, but are not limited to, docetaxelinjections, such as Taxotere®; paclitaxel injections, such asPaclitaxel® and mitoxantrone injections, such as Novantrone®. Also, theadditional therapeutic agent can be in the form of depots or implantssuch as leuprolide depots and implants, e.g. Viadur® and Lupron Depot®;triptorelin depots. e.g. Trelstar®; goserelin implants, e.g. Zoladex®.

The suitable daily dosage of the 17α-hydroxylase/C_(17,20)-lyaseinhibitor depends upon a number of factors, including, the nature of theseverity of the condition to be treated, the particular inhibitor, theroute of administration and the age, weight, and response of theindividual patient. Suitable daily dosages of17α-hydroxylase/C_(17,20)-lyase inhibitors can generally range fromabout 0.0001 mg/kg/day to about 1000 mg/kg/day, or from about 0.001mg/kg/day to about 200 mg/kg/day, or from about 0.01 mg/kg/day to about200 mg/kg/day, or from about 0.01 mg/kg/day to about 100 mg/kg/day insingle or multiple doses.

In some embodiments, the 17α-hydroxylase/C_(17,20)-lyase inhibitor canbe administered in an amount from about 0.004 mg/day to about 5,000mg/day, or from about 0.04 mg/day to about 3,000 mg/day, or from about0.4 mg/day to about 1500 mg/day. In certain embodiments, the17α-hydroxylase/C_(17,20)-lyase inhibitor can be administered in anamount from about 0.1 mg/day to about 2000 mg/day or from about 1 mg/dayto about 2000 mg/day or from about 50 mg/day to about 2000 mg/day orfrom about 100 mg/day to about 1500 mg/day or from about 5 mg/day toabout 1,000 mg/day or from about 5 mg/day to about 900 mg/day or fromabout 10 mg/day to about 800 mg/day or from about 15 mg/day to about 700mg/day or from about 20 mg/day to about 600 mg/day or from about 25mg/day to about 500 mg/day in single or multiple doses.

In certain embodiments, the 17α-hydroxylase/C_(17,20)-lyase inhibitor isco-administered with an additional anti-cancer agent such asmitoxantrone, paclitaxel or docetaxel. For example, a method for thetreatment of a cancer in a mammal comprises administering an amount ofabiraterone acetate and an amount of mitoxantrone. For example, theabiraterone acetate can be administered in an amount of about 0.01mg/kg/day to about 100 mg/kg/day and the mitoxantrone can beadministered in an amount of about 0.1 mg/m² to about 20 mg/m².Preferably, the mitoxantrone is administered over a period of betweenabout 10 to about 20 minutes once every 21 days.

Also, a method for the treatment of a cancer in a mammal can compriseadministering an amount of abiraterone acetate and an amount ofpaclitaxel. In one embodiment, the abiraterone acetate can beadministered in an amount of about 0.01 mg/kg/day to about 100 mg/kg/dayand the paclitaxel can be administered in the amount of about 1 mg/m toabout 175 mg/m². Preferably, the paclitaxel is administered over aperiod of between about 2 to about 5 hours once every three months.

Additionally, a method for the treatment of a cancer in a mammalcomprises administering an amount of abiraterone acetate and an amountof docetaxel. For example, the abiraterone acetate can be administeredin an amount of about 0.01 mg/kg/day to about 100 mg/kg/day and thedocetaxel can be administered in an amount of about 1 mg/m² to about 100mg/m². Preferably, the docetaxel is administered over a period ofbetween about 1 to about 2 hours once every three weeks.

In certain embodiments, the 17α-hydroxylase/C_(17,20)-lyase inhibitor isadministered along with an anti-cancer agent that comprises a hormonalablation agent, including, but not limited to, leuprolide, goserelin, ortriptorelin. For example, one method for the treatment of a cancer in amammal also comprises administering an amount of abiraterone acetate andan amount of leuprolide. The amount of abiraterone acetate can be about0.01 mg/kg/day to about 100 mg/kg/day and the amount of leuprolide canbe about 0.01 mg to about 200 mg over a period of about 3 days to about12 months. Preferably, the leuprolide is administered in the amount ofabout 3.6 mg of leuprolide over a period of about 3 days to about 12months.

Additionally, the methods for the treatment of cancer in a mammalinclude administering an amount of abiraterone acetate and an amount ofgoserelin. For example, the amount of abiraterone acetate can be about0.01 mg/kg/day to about 100 mg/kg/day and the amount of goserelin can beabout 0.01 mg to about 20 mg over a period of about 28 days to about 3months. Preferably, the goserelin is administered in the amount of about3.6 mg to about 10.8 mg over a period of about 28 days to about 3months.

In certain embodiments the methods for the treatment of cancer in amammal comprises administering an amount of abiraterone acetate and anamount of triptorelin. For example, the amount of abiraterone acetatecan be about 0.01 mg/kg/day to about 100 mg/kg/day and the amount oftriptorelin can be about 0.01 mg to about 20 mg, over a period of about1 month, preferably the triptorelin is administered in the amount ofabout 3.75 mg over a period of about 1 month.

Also, in one embodiment, the method for the treatment of a cancer in amammal comprises administering an amount of abiraterone acetate and anamount of seocalcitol. For instance, the method involves administeringan amount of about 0.01 mg/kg/day to about 100 mg/kg/day of abirateroneacetate and an amount of about 0.1 μg/day to about 500 μg/day ofseocalcitol, such as about 100 μg/day of seocalcitol.

In another embodiment, the method for the treatment of a cancer in amammal comprises administering an amount of abiraterone acetate and anamount of bicalutamide. For instance, the method involves administeringan amount of about 0.01 mg/kg/day to about 100 mg/kg/day of abirateroneacetate and an amount of about 1 mg/day to about 300 mg/day ofbicalutamide.

In yet another embodiment, the method for the treatment of a cancer in amammal comprises administering an amount of abiraterone acetate and anamount of flutamide. For example, the method comprises administering anamount of about 0.01 mg/kg/day to about 100 mg/kg/day of abirateroneacetate and an amount of about 1 mg/day to about 2000 mg/day offlutamide.

Moreover, the method for the treatment of a cancer in a mammal cancomprise administering an amount of a 17α-hydroxylase/C_(17,20)-lyaseinhibitor such as abiraterone acetate and an amount of a glucocorticoidincluding, but not limited to, hydrocortisone, prednisone ordexamethasone. For example, the method can comprise administering anamount of about 50 mg/day to about 2000 mg/day of abiraterone acetateand an amount of about 0.01 mg/day to about 500 mg/day ofhydrocortisone. In other instances, the method can compriseadministering an amount of about 500 mg/day to about 1500 mg/day ofabiraterone acetate and an amount of about 10 mg/day to about 250 mg/dayof hydrocortisone.

The method for the treatment of a cancer can also comprise administeringan amount of a 17α-hydroxylase/C_(17,20)-lyase inhibitor, such asabiraterone acetate, and an amount of a glucocorticoid, such asprednisone. For example, the method can comprise administering an amountof about 50 mg/day to about 2000 mg/day of abiraterone acetate and anamount of about 0.01 mg/day to about 500 mg/day of prednisone. Also, themethod can comprise administering an amount of about 500 mg/day to about1500 mg/day of abiraterone acetate and an amount of about 10 mg/day toabout 250 mg/day of prednisone.

In addition, the method for the treatment of a cancer can also compriseadministering an amount of a 17α-hydroxylase/C_(17,20)-lyase inhibitor,such as abiraterone acetate, and an amount of a glucocorticoid, such asdexamethasone. For example, the method can comprise administering anamount of about 50 mg/day to about 2000 mg/day of abiraterone acetateand an amount of about 0.01 mg/day to about 500 mg/day of dexamethasone.Also, the method can comprise administering an amount of about 500mg/day to about 1500 mg/day of abiraterone acetate and an amount ofabout 0.5 mg/day to about 25 mg/day of dexamethasone.

Compositions Containing a 17α-hydroxylase/C_(17,20)-lyase Inhibitor andan Additional Therapeutic Agent

In certain embodiments, the compositions can contain a combination of a17α-hydroxylase/C_(17,20)-lyase inhibitor, preferably abirateroneacetate, and any of the therapeutic agents recited above. Whether the17α-hydroxylase/C_(17,20)-lyase inhibitor and the additional therapeuticagent are administered in separate compositions or as a singlecomposition, the compositions can take various forms. For example, thecompositions can take the form of solutions, suspensions, emulsions,tablets, pills, capsules, powders or sustained-release formulations,depending on the intended route of administration.

For topical or transdermal administration, the compositions can beformulated as solutions, gels, ointments, creams, suspensions or salves.

For oral administration, the compositions may be formulated as tablets,pills, dragees, troches, capsules, liquids, gels, syrups, slurries,suspensions and the like, for oral ingestion by a patient to be treated.

The composition may also be formulated in rectal or vaginal compositionssuch as suppositories or retention enemas that contain conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compositionmay also be formulated as a depot preparation. Such long actingformulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the therapeutic agents may be formulated with suitablepolymeric or hydrophobic materials (for example as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly solublederivatives, for example, as a sparingly soluble salt.

Additionally, the composition may be delivered using a sustained-releasesystem, such as semi-permeable matrices of solid polymers containing thecomposition. Various forms of sustained-release materials have beenestablished and are well known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature canrelease the composition over a period of hours, days, weeks, months. Forexample a sustained release capsule can release the compositions over aperiod of 100 days or longer. Depending on the chemical nature and thebiological stability of the composition, additional strategies forstabilization may be employed.

The compositions can further comprise a pharmaceutically acceptablecarrier. The term “carrier” refers to a diluent, adjuvant (e.g.,Freund's adjuvant (complete and incomplete)), excipient, or vehicle withwhich the therapeutic is administered.

For parenteral administrations, the composition can comprise one or moreof the following carriers: a sterile diluent such as water forinjection, saline solution, fixed oils, polyethylene glycols, glycerin,propylene glycol or other synthetic solvents; antibacterial agents suchas benzyl alcohol or methyl parabens; antioxidants such as ascorbic acidor sodium bisulfite; chelating agents such as ethylenediaminetetraaceticacid; buffers such as acetates, citrates or phosphates and agents forthe adjustment of tonicity such as sodium chloride or dextrose. Theparenteral preparation can be enclosed in ampules, disposable syringesor multiple dose vials made of glass or plastic.

For oral solid formulations suitable carriers include fillers such assugars, e.g., lactose, sucrose, mannitol and sorbitol; cellulosepreparations such as maize starch, wheat starch, rice starch, potatostarch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, fats andoils; granulating agents; and binding agents such as microcrystallinecellulose, gum tragacanth or gelatin; disintegrating agents, such ascross-linked polyvinylpyrrolidone, agar, or alginic acid or a saltthereof such as sodium alginate, Primogel, or corn starch; lubricants,such as magnesium stearate or Sterotes; glidants, such as colloidalsilicon dioxide; a sweetening agent, such as sucrose or saccharin; orflavoring agents, such as peppermint, methyl salicylate, or orangeflavoring. If desired, solid dosage forms may be sugar-coated orenteric-coated using standard techniques.

For intravenous administration, suitable carriers include physiologicalsaline, bacteriostatic water, phosphate buffered saline (PBS). In allcases, the composition must be sterile and should be fluid to the extentthat easy injectability with a syringe. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol, andliquid polyethylene glycol, and the like), and suitable mixturesthereof. The proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prevention of the action of microorganisms can be achieved by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it will be preferable to include isotonic agents, for example,sugars; polyalcohols such as mannitol, sorbitol; sodium chloride in thecomposition. Prolonged absorption of the injectable compositions can bebrought about by including in the composition an agent which delaysabsorption, for example, aluminum monostearate and gelatin.

Also for intravenous administration, the compositions may be formulatedin solutions, preferably in physiologically compatible buffers such asHanks's solution, Ringer's solution, or physiological saline buffer. Thesolution may contain formulatory agents such as suspending, stabilizingand/or dispersing agents. In a preferred embodiment, the compositionsare formulated in sterile solutions.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art, and include, for example, for transmucosaladministration, detergents, bile salts, and fusidic acid derivatives.Transmucosal administration can be accomplished through the use of nasalsprays or suppositories.

For administration by inhalation, the compositions may be formulated asan aerosol spray from pressurized packs or a nebulizer, with the use ofa suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Capsules and cartridges of gelatin for use in an inhaler or insufflatormay be formulated containing a powder mix of the composition and asuitable powder base such as lactose or starch.

The pharmaceutical compositions may be manufactured by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or lyophilizing processes.

One example of a composition comprising a17α-hydroxylase/C_(17,20)-lyase inhibitor and an additional therapeuticagent is an oral composition or composition suitable for oraladministration comprising abiraterone acetate in combination with asteroid. For example, the oral composition can be a solid dosage formsuch as a pill, a tablet or a capsule. The oral composition can compriseabout 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750mg, 800 mg, 850 mg, 900 mg, 950 mg, or 1000 mg of abiraterone acetate.The oral composition can comprises about 0.25 mg, 0.5 mg 0.75 mg, 1.0mg, 1.25 mg, 1.5 mg, 1.75 ng, 2.0 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3.0 mg,3.25 mg, 3.5 mg, 3.75 mg, 4.0 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5.0 mg, 7.5mg, 10 mg, 20 mg, 30 mg, 40 mg or 50 mg of a steroid, such as aglucocorticoid.

In one embodiment, the oral composition can comprise about 50 mg toabout 500 mg of abiraterone acetate and an amount of about 0.25 mg toabout 3.5 mg of the steroid, such as hydrocortisone, prednisone ordexamethasone. In other instances, the composition can comprise about 50mg to about 300 mg of abiraterone acetate and an amount of about 1.0 mgto about 2.5 mg of the steroid, such as hydrocortisone, prednisone ordexamethasone. In another embodiment the composition can comprise about50 ing to about 300 mg of abiraterone acetate and about 0.5 mg to about3.0 mg of a steroid. For example, the oral composition can be a tabletcontaining 250 mg of abiraterone acetate; 1.25 mg or 2.0 mg of asteroid, such as hydrocortisone, prednisone or dexamethasone; and one ormore carriers, excipients, diluents or additional ingredients.Additionally, the oral composition can be a capsule containing 250 mg ofabiraterone acetate; 1.25 mg or 2.0 mg of a steroid, such ashydrocortisone, prednisone or dexamethasone; and one or more carriers,excipients, diluents or additional ingredients.

The description contained herein is for purposes of illustration and notfor purposes of limitation. The methods and compositions describedherein can comprise any feature described herein either alone or incombination with any other feature(s) described herein. Changes andmodifications may be made to the embodiments of the description.Furthermore, obvious changes, modifications or variations will occur tothose skilled in the art. Also, all references cited above areincorporated herein, in their entirety, for all purposes related to thisdisclosure.

1-86. (canceled)
 87. A method for the treatment of a prostate cancer ina human comprising administering to said human a therapeuticallyeffective amount of abiraterone acetate or a pharmaceutically acceptablesalt thereof and a therapeutically effective amount of dexamethasone.88. The method of claim 87, wherein the therapeutically effective amountof the abiraterone acetate or pharmaceutically acceptable salt thereofis from about 50 mg/day to about 2000 mg/day.
 89. The method of claim88, wherein the therapeutically effective amount of the abirateroneacetate or pharmaceutically acceptable salt thereof is from about 500mg/day to about 1500 mg/day.
 90. The method of claim 89, wherein thetherapeutically effective amount of the abiraterone acetate orpharmaceutically acceptable salt thereof is about 1000 mg/day.
 91. Themethod of claim 87, wherein the therapeutically effective amount of theabiraterone acetate or a pharmaceutically acceptable salt thereof isadministered in at least one dosage form comprising about 250 mg ofabiraterone acetate or a pharmaceutically acceptable salt thereof. 92.The method of claim 87, wherein the therapeutically effective amount ofthe dexamethasone is from about 0.01 mg/day to about 500 mg/day.
 93. Themethod of claim 92, wherein the therapeutically effective amount of thedexamethasone is from about 0.5 mg/day to about 25 mg/day.
 94. Themethod of claim 93, wherein the therapeutically effective amount of thedexamethasone is about 0.5 mg/day.
 95. The method of claim 87,comprising administering to said human about 500 mg/day to about 1500mg/day of abiraterone acetate or a pharmaceutically acceptable saltthereof and about 0.5 mg/day to about 25 mg/day of dexamethasone. 96.The method of claim 95, comprising administering to said human about1000 mg/day of abiraterone acetate or a pharmaceutically acceptable saltthereof and about 0.5 mg/day of dexamethasone.
 97. The method of claim87, wherein said prostate cancer is refractory prostate cancer.
 98. Themethod of claim 97, wherein the refractory prostate cancer is notresponding to at least one anti-cancer agent.
 99. The method of claim98, wherein the at least one anti-cancer agent comprises a hormonalablation agent, an anti-androgen agent, or an anti-neoplastic agent.100. The method of claim 99, wherein the hormonal ablation agentcomprises deslorelin, leuprolide, goserelin, or triptorelin.
 101. Themethod of claim 99, wherein the anti-androgen agent comprisesbicalutamide, flutamide, or nilutamide.
 102. The method of claim 99,wherein the anti-neoplastic agent comprises docetaxel.
 103. The methodof claim 98, comprising administering to said human about 500 mg/day toabout 1500 mg/day of abiraterone acetate or a pharmaceuticallyacceptable salt thereof and about 0.5 mg/day to about 25 mg/day ofdexamethasone.
 104. The method of claim 103, comprising administering tosaid human about 1000 mg/day of abiraterone acetate or apharmaceutically acceptable salt thereof and about 0.5 mg/day ofdexamethasone.